In principle, contrast-enhanced magnetic resonance (MR) imaging is capable of non-invasively measuring regional myocardial perfusion, blood volume, extracellular volume, and capillary permeability. In practice, these potential applications are difficult to achieve due to a lack of knowledge concerning the relationship between myocardial contrast concentration and the observed changes in image pixel intensity. Like other imaging modalities, such as PET and CT, the interpretation of myocardial MR contrast enhancement depends on understanding the myocardial kinetics of the tracer. Unlike other modalities, however, interpretation of MR contrast enhancement also requires knowledge of the extent of interaction between the contrast molecule and the myocardial protons (mostly water) from which the MR signal is derived. This interaction is fundamentally linked to myocardial physiology. Historically, most studies of myocardial contrast enhancement have either avoided addressing this interaction by drawing strictly qualitative conclusions or have made broad assumptions concerning this interaction. In this proposal, we present data which demonstrate that myocardial relaxivity (T1) enhancement is directly and profoundly influenced by the diffusion of water between the myocardial vascular, interstitial, and cellular compartments. We also present data which demonstrate our ability to test hypotheses concerning the mechanisms of susceptibility contrast directly in myocardial tissue. We propose a five-year research plan to fully describe both relaxivity and susceptibility myocardial contrast enhancement on the basis of the underlying physiology. We believe that by directly addressing and understanding the effects of myocardial physiology on MR contrast enhancement we will be able to fully evaluate not only the potential of contrast MR to reproduce the successes of PET and CT, but the unique potential of MR contrast enhancement to provide additional physiologic information based on the influence of tissue environment on the MR signal.